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A novel role of thrombospondin-1 in cervical carcinogenesis: inhibit stroma reaction by inhibiting activated fibroblasts from invading cancer.
- Source :
-
Carcinogenesis [Carcinogenesis] 2008 Jun; Vol. 29 (6), pp. 1115-23. Date of Electronic Publication: 2008 Apr 15. - Publication Year :
- 2008
-
Abstract
- Thrombospondin (TSP)-1, a potent angiogenesis inhibitor, has been shown to exert different biological functions on various cell types. Here, we investigate the role of TSP-1 in tumor-stroma reaction, which is mainly characterized by fibroblast activation to create a permissive microenvironment for tumor progression. Immunohistochemistry examinations in the human surgical specimens have shown that a downregulation of TSP-1 during the progression of cervical carcinogenesis was accompanied by an emergence in the upregulation of stroma markers, alpha-smooth muscle actin (alpha-SMA) and desmin. Transfection of SiHa cervical cancer cells with a plasmid expressing the TSP-1 protein exhibited antiangiogenic activity in vitro and resulted in reduced tumor growth in severe combined immunodeficiency (SCID) mice, which was accompanied by a decrease in tumor vascularization and lower expressions of alpha-SMA and desmin than those in the vector controls. Transfection with TSP-1 and purified TSP-1 added to NIH3T3 cells did not alter the protein levels of alpha-SMA and desmin but significantly inhibited matrix metalloprotease-2 activity. Transforming growth factor-beta (TGF-beta), a major factor in the activation of fibroblasts, increased alpha-SMA and desmin expression and the ability of cell migration and invasion in NIH3T3 cells. The increased migration ability and the invasive ability into tumor cluster of TGF-beta-treated NIH3T3 cells were dose dependently inhibited by TSP-1. In contrast, ectopic TSP-1 expression in SiHa cells has little effect on the invasive ability of the NIH3T3 cells. Together, our findings demonstrate a novel role of TSP-1 to inhibit tumor-stroma reaction that could be attributed to the blockage of activated fibroblasts from invading cancer cells.
- Subjects :
- Actins metabolism
Animals
Cell Movement physiology
Cells, Cultured
Desmin metabolism
Female
Humans
Immunoblotting
Immunohistochemistry
Matrix Metalloproteinase 2 metabolism
Mice
Neovascularization, Pathologic metabolism
Neovascularization, Pathologic pathology
Transfection
Uterine Cervical Neoplasms metabolism
Fibroblasts metabolism
Neoplasm Invasiveness pathology
Thrombospondin 1 metabolism
Uterine Cervical Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2180
- Volume :
- 29
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Carcinogenesis
- Publication Type :
- Academic Journal
- Accession number :
- 18413367
- Full Text :
- https://doi.org/10.1093/carcin/bgn077